A phase II 'window' study of topotecan in untreated patients with high risk adult acute lymphoblastic leukemia

Steven D. Gore, Eric K. Rowinsky, Carole B. Miller, Constance Griffin, Tian Ling Chen, Michael Borowitz, Ross C. Donehower, Kathleen L. Burks, Deborah K. Armstrong, Philip J. Burke, Michael R. Grever, Scott H. Kaufmann

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15 Scopus citations

Abstract

To further evaluate the activity of topotecan (TPT) in acute leukemia, TPT was administered (2.1 mg/m2/day for 5 days by continuous i.v. infusion) to adult patients with previously untreated acute lymphoblastic leukemia (ALL) with high-risk features (13 patients) or relapsed ALL (1 patient). Patients achieving a partial response or significant hematological improvement received a second course. All patients subsequently received standard treatment for ALL. Because complete response was achieved in only 1 of 14 patients, the study was terminated prematurely. An additional patient achieved minimal response, and a third patient normalized her hemogram despite ongoing leukemia in the marrow. Overall, six patients had significant hematological improvement (normalization of platelet and/or absolute neutrophil count). Two patients expired due to infections during induction chemotherapy. The primary nonhematological toxicities were mucositis and diarrhea. Exposure to TPT did not appear to influence the response to subsequent standard chemotherapy. The mean steady-state TPT plasma concentration, 16.1 ± 1 nM, overlapped the range of LD90 values of primary human leukemia specimens. Cellular topo I content varied over a 3-fold range, encompassing levels found previously in relapsed patients. No relationship was found between topo I expression and markers of cellular proliferation or response to therapy. In contrast, low expression of the apoptosis inhibitor Bcl-2 was associated with response to TPT therapy. TPT has significant, albeit modest, single-agent activity against high-risk adult ALL. This study demonstrates the feasibility of evaluating promising new therapeutic agents in untreated patients with acute leukemia at high risk for failure with conventional therapy.

Original languageEnglish (US)
Pages (from-to)2677-2689
Number of pages13
JournalClinical Cancer Research
Volume4
Issue number11
StatePublished - Nov 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gore, S. D., Rowinsky, E. K., Miller, C. B., Griffin, C., Chen, T. L., Borowitz, M., Donehower, R. C., Burks, K. L., Armstrong, D. K., Burke, P. J., Grever, M. R., & Kaufmann, S. H. (1998). A phase II 'window' study of topotecan in untreated patients with high risk adult acute lymphoblastic leukemia. Clinical Cancer Research, 4(11), 2677-2689.